Search

Immune checkpoint inhibitors (ICIs) improve outcomes in advanced melanoma, but many patients are refractory or experience relapse. The gut microbiota modulates antitumor responses. However, inconsistent baseline predictors point to heterogeneity in responses and inadequacy of cross-sectional data. We followed patients with unresectable melanoma from baseline and during anti-PD-1 therapy, collecting fecal and blood samples that were surveyed for changes in the gut microbiota and immune markers. Varying patient responses were linked to different gut microbiota dynamics during ICI treatment. We select complete responders by their stable microbiota functions and validate them using multiple external cohorts and experimentally. We identify major histocompatibility complex class I (MHC class I)-restricted peptides derived from flagellin-related genes of Lachnospiraceae (FLach) as structural homologs of tumor-associated antigens, detect FLach-reactive CD8 + T cells in complete responders before ICI therapy, and demonstrate that FLach peptides improve antitumor immunity. These findings highlight the prognostic value of microbial functions and therapeutic potential of tumor-mimicking microbial peptides., Competing Interests: Declaration of interests L.N., T.M., P.A.A., and A.D.G.M. are named co-inventors on a patent application relating to this work (EP n. 24164184.4 “Flagellin-related peptides and uses”). M.C.A. reports advisory board participation, honoraria, or research funds to institutions from MSD Australia, BMS Australia, and Pierre Fabre Australia and is a named co-inventor on a patent application relating to Methods and compositions for treating cancer (WO2020106983A1), all unrelated to this work. P.A.A. reports grants or contracts from Bristol Myers Squibb, Roche-Genentech, Pfizer, and Sanofi; consulting fees from Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, Sun Pharma, Sanofi, Sandoz, Italfarmaco, Nektar, Pfizer, Lunaphore, Medicenna, Bio-Al Health, ValoTx, Replimmune, and Bayer; support for attending meetings and/or travel from Pfizer, Bio-Al Health, and Replimmune; and participating on a data safety monitoring board or advisory board for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, AstraZeneca, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos, and Erasca. L.N. reports research funds from BMS Europe unrelated to this work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mucosal melanoma (MucM) is a rare cancer with a poor prognosis and low response rate to immune checkpoint inhibition (ICI) compared with cutaneous melanoma (CM). To explore the immune microenvironment and potential drivers of MucM's relative resistance to ICI drugs, we characterized 101 MucM tumors (43 head and neck [H&N], 31 female urogenital, 13 male urogenital, 11 anorectal, and 3 other gastrointestinal) using bulk RNA-Seq and immunofluorescence. RNA-Seq data show that MucM has a significantly lower IFN-γ signature levels than CM. MucM tumors of the H&N region show a significantly greater abundance of CD8+ T cells, cytotoxic cells, and higher IFN-γ signature levels than MucM from lower body sites. In the subcohort of 35 patients with MucM treated with ICI, hierarchical clustering reveals clusters with a high and low degree of immune infiltration, with a differential ICI response rate. Immune-associated gene sets were enriched in responders. Signatures associated with cancer-associated fibroblasts, macrophages, and TGF-β signaling may be higher in immune-infiltrated, but ICI-unresponsive tumors, suggesting a role for these resistance mechanisms in MucM. Our data show organ region-specific differences in immune infiltration and IFN-γ signature levels in MucM, with H&N MucM displaying the most favorable immune profile. Our study might offer a starting point for developing more personalized treatment strategies for this disease.

Introduction: Approximately 50 % of resected stage II-IV melanoma patients develop recurrent disease by 5 years despite adjuvant anti-PD-1 therapy. Data to define best management of recurrences is lacking., Methods: This was a multicentre, international, retrospective cohort study. Patients with resected stage II-IV melanoma who commenced adjuvant anti-PD-1-based therapy before January 2022 and later recurred were identified. Data on demographics, disease characteristics, recurrence patterns, management and outcomes were collected., Results: 711 patients from 17 sites were included. Median age was 60 [range 16-92], 64 % were male, 2 % stage II, 91 % were stage III, 7 % stage IV. Median time to recurrence was 6.2 months (0-68.5) and median follow up time from recurrence was 19.8 months (range 0.2-73.1). 63 % recurred on anti-PD-1 therapy, 36 % off therapy [3 % < 6 months, 33 % > 6 months]. Initial recurrences were locoregional (LR) alone in 44 %, distant alone (DR) in 43 %, and 11 % in both sites. LR recurrences were managed with local therapy, alone (62 %) or with "second adjuvant" anti-PD-1 (14 %) or BRAF/MEK therapy (23 %); 12 m RFS2 was 25 %, 29 % and 69 % respectively (p = 0.0045). Definitive systemic therapy at first recurrence was given in 16 % LR and 86 % DR, with best outcomes for anti-CTLA4 + anti-PD-1 and trial combinations (24 m PFS 63 % and 69 %, respectively). The 24 m OS for the entire cohort was 65 %., Conclusion: Most recurrences following adjuvant anti-PD-1 based therapy occur early and while still on drug. Outcomes are poor, regardless of site, timing of recurrence, and subsequent treatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, and Qbiotics. JK has received research funding from LEO Pharma, honorium from BMS, Amgen, Janssen; and educational funding from MSD, Janssen and Astra Zeneca. RRT has served on advisory boards for BMS, MSD, Amgen, Pierre-Fabre, Astra Zeneca and Roche. CL has received research funding from BMS, Roche, consulting fees from BMS, Pierre-Fabre, Sanofi, Novartis, MSD, Amgen, Merck Serono, Roche and Iflax; speaking fees from Amgen, BMS, Pierre-Fabre, Sanofi, Novartis, MSD, Incyte, Pfizer, Roche; and travel funding from BMS, MSD, Novartis, Pierre-Fabre, Roche, Sanofi and served on advisory boards for BMS, Pierre Fabre, Sanofi, Novartis, MSD, Magen, Merck Serono, Roche and Inflax. CA has received travel funding from BMS, Roche and Amgen and speaking fees from Novartis. RJS has served on advisory boards for Merck, Novartis, Pfizer, and Replimune and receives grant funding from Merck. CR has served on advisory boards for Pierre Fabre, Sanofi, BMS, MSD, Novartis, Merck, Roche, Pfizer, Sun Pharma, Ultimovacs, Regeneron, Egle, Philogen, Maat Pharma; involved in steering committees for Novartis, Regeneron, Pfizer and IO Biotech and a consultant IDMC for Ultimovacs; received speaking fees from Pierre Fabre, Sanofi, BMS, MSD and Novartis and travel funding from Pierre Fabre. JM has intermittent project focused consultant or advisory relationships with Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Johnson & Johnson, and Pierre Fabre and has received travel support from L′ Oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. MSC has served on advisory boards or as a consultant for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi and received honoraria from BMS, MSD, and Novartis. DBJ has served on advisory boards or as a consultant for AstraZeneca, BMS, The Jackson Laboratory, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte. BN has received financial compensation from Novartis, Roche, BMS, MSD, and Pierre-Fabre for service on advisory boards and speaking engagements; and institutional research funding from Pfizer, Novartis, Roche and Merck-Serono. VR has received honoraria from AstraZeneca and has received travel and education funding from MSD and Novartis. PAA has served as a consultant for BMS, MSD, Roche-Genentech, Ventana, Novartis, Amgen and Array and received research funding from BMS, Roche-Genentech and Ventana. JW has served as a consultant for Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, Moderna, ImCheck, Sellas, Evaxion, Pfizer, Regeneron, EMD Serono, and Bristol Myers Squibb; has had equity roles in Biond, Evaxion, OncoC4, and Instill Bio; received institutional research support from Bristol Myers Squibb, Merck, GSK, Moderna, Pfizer, Novartis, and AstraZeneca; served in scientific advisory roles with CytomX, Incyte, ImCheck, Biond, Sellas, Instill Bio, OncoC4, and NexImmune; and holds patent agreements with Moffitt Cancer Center and Biodesix. PR has received honoraria from BMS, MSD, Novartis, Pierre-Fabre, Merck and Sanofi; and served in an advisory capacity for MSD, BMS, Sanofi, Pierre-Fabre, Blueprint Medicines and Philogen. GAM has received institutional research funding through Roche-Genentech, MSD, Roche, and BMS and other funding through Novartis and BMS. SH has served as a consultant for Amgen, Genmab, Xencor, Astellas Pharma, Regeneron, and Nektar. AA has served as a consultant for BMS, Roche, Novartis, Pierre Fabre, MSD, Merck, Sanofi; received speaking fees from Pierre Fabre, Novartis, MSD, BMS, Roche, Merck, Sanofi; institutional funding from Pierre-Fabre, Novartis, Roche, BMS, MSD, Merck and Sanofi; and travel funding from BMS, MSD, Novartis, Pierre-Fabre. AH has served on an advisory board for BMS, MSD and Novartis. RD has received honoraria from Roche, Novartis, Bristol Myers Squibb, MSD, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Regeneron, Alligator Bioscience, MaxiVax, touchIME, T3 Pharmaceuticals, Pfizer; served as a consultant for Roche, Bristol Myers Squibb, MSD, Novartis, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Alligator Bioscience, touchIME, MaxiVax, Regeneron, Pfizer, T3 Pharmaceuticals and received institutional research funding from Roche, BMS, Novartis, MSD and Amgen. CUB has served as a consultant for AstraZeneca, Bristol-Myers Squibb, GenMab, GlaxoSmithKline, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Third Rock Ventures; received institutional research funding from SC, Bristol-Myers Squibb, NanoString Technologies, and Novartis; provided expert testimony for Freshfields Bruckhaus Deringer; received travel funding from BMS; and has ownership interest in Immagene and Signature Oncology. GVL has received honoraria from BMS, Pierre-Fabre and received served as a consultant for Agenus, Amgen, Array BioPharma, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion Biotech, Hexal AG (Sandoz Company), Highlight Therapeutics, Innovent Biologics USA Inc, Merck Sharp & Dohme, Novartis, OncoSec Medical Australia, PHMR Limited, Pierre Fabre, Provectus, QBiotics, Regeneron, and AstraZeneca. The remaining authors have nothing to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Previous studies demonstrated limited efficacy of immune checkpoint inhibitors in unresectable acral melanoma (AM); it remains unclear how this translates to the adjuvant setting. This study investigates clinical outcomes of acral compared to cutaneous melanoma (CM) patients treated with adjuvant anti-PD-1 after complete resection. All stages III-IV AM and CM patients receiving adjuvant anti-PD-1 after complete resection between 2018 and 2022 were included from the prospective nationwide Dutch Melanoma Treatment Registry. We analyzed recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). A multivariable Cox regression analysis of RFS was performed to adjust for potential confounders. We included 1958 (86 AM and 1872 CM) patients. At baseline, AM patients more frequently had KIT mutations, higher disease stages, and Eastern Cooperative Oncology Group Performance Status, and fewer BRAF and NRAS mutations. Median RFS was 14.8 months (95% confidence interval [CI]: 11.5-29.3) in AM and 37.4 months (95% CI: 34.6 to not reached) in CM (p = .002). After correcting for potential confounders, AM remained associated with a higher risk of recurrence (HR adj 1.53; 95% CI: 1.07-2.17; p = .019). Two-year DMFS tended to be worse for AM than for CM: 64.5% versus 79.7% (p = .050). Two-year OS was significantly lower in AM (71.5% vs. 84.3%; p = .027). The results of this study suggest a poorer outcome of adjuvant-treated AM compared to CM. Studies assessing the added value of adjuvant treatment in AM are needed. Future research should investigate alternative treatment strategies to improve outcomes of high-risk AM., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8 + T cells and exhausted CD8 + T cell (T EX ) clones. Focused analyses of T EX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor T EX , which synergizes with anti-PD-1 to reinvigorate T EX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies., Competing Interests: Declaration of interests A.C.H. performed consulting work for Immunai and received research funding from Bristol Myers Squibb and Merck. R.S.H. has performed consulting work for Bristol Myers Squibb (exclusive of the current work). T.C.M. received honorarium for Scientific Advisory Board participation from: BMS, GigaGen, Merck, Pliant, Pfizer. G.C.K. is on the Merck Advisory Board. J.W. consulted for and have received less than $10,000 per annum from Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, Moderna, ImCheck, Sellas, Evaxion, Pfizer, Regeneron, and EMD Serono and received $10–$25,000 from BMS for membership on advisory boards. J.W. also holds equity in Biond, Evaxion, OncoC4, and Instil Bio, and on scientific advisory boards for CytomX, Incyte, ImCheck, Biond, Sellas, Instil Bio, OncoC4, and NexImmune and remunerated between $10,000–$50,000. In addition, J.W. is named on a patent filed by Moffitt Cancer Center on an ipilimumab biomarker and on TIL preparation and also on a PD-1 patent filed by Biodesix; J.W. receives less than $6000 in royalties. D.B., E.K., and C.S. were employed by Immunai when engaged in this project. S.G. and D.T. are employees of BMS. C.A. is a consultant for Biotherapy Partners., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: Long-term survival data from clinical trials show that survival curves of patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs) gradually reach a plateau, suggesting that patients have a chance of achieving long-term survival., Objective: To investigate long-term survival in patients with advanced melanoma treated with ICIs outside clinical trials., Design, Setting, and Participants: Cohort study using prospectively collected data from the nationwide Dutch Melanoma Treatment Registry, including patients in the Netherlands with advanced melanoma treated with first-line ICIs from 2012 to 2019. Data were analyzed from January to September 2023., Exposures: Patients were treated with first-line ipilimumab-nivolumab, antibodies that target programmed cell death (anti-PD-1), or ipilimumab., Main Outcomes and Measures: Progression-free survival (PFS) and melanoma-specific survival were analyzed, and a Cox proportional hazards model was used to investigate factors associated with PFS after reaching partial response (PR) or complete response (CR)., Results: A total of 2490 patients treated with first-line ICIs were included (median [IQR] age, 65.0 [55.3-73.0] years; 1561 male patients [62.7%]). Most patients had an Eastern Cooperative Oncology Group Performance Status of 1 or lower (2202 patients [88.5%]) and normal lactate dehydrogenase levels (1715 patients [68.9%]). PFS for all patients was 23.4% (95% CI, 21.7%-25.2%) after 3 years and 19.7% (95% CI, 18.0%-21.4%) after 5 years. Overall survival for all patients was 44.0% (95% CI, 42.1%-46.1%) after 3 years and 35.9% (95% CI, 33.9%-38.0%) after 5 years. Patients with metastases in 3 or more organ sites had a significantly higher hazard of progression after reaching PR or CR (adjusted hazard ratio, 1.37; 95% CI, 1.11-1.69)., Conclusions and Relevance: This cohort study of patients with advanced melanoma treated with ICIs in clinical practice showed that their survival reached a plateau, comparable with patients participating in clinical trials. These findings can be used in daily clinical practice to guide long-term surveillance strategies and inform both physicians and patients regarding long-term treatment outcomes.

Background: Recent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus far, we assessed the association of immunosuppressant type and dose with survival in melanoma patients with irAEs., Methods: Patients with advanced melanoma who received immunosuppressants for irAEs induced by first-line anti-PD-1 ± anti-CTLA-4 were included from 18 hospitals worldwide. Associations of cumulative and peak dose corticosteroids and use of second-line immunosuppression with survival from start of immunosuppression were assessed using multivariable Cox proportional hazard regression., Results: Among 606 patients, 404 had anti-PD-1 + anti-CTLA-4-related irAEs and 202 had anti-PD-1-related irAEs. 425 patients (70 %) received corticosteroids only; 181 patients (30 %) additionally received second-line immunosuppressants. Median PFS and OS from starting immunosuppression were 4.5 (95 %CI 3.4-8.1) and 31 (95 %CI 15-not reached) months in patients who received second-line immunosuppressants, and 11 (95 %CI 9.4-14) and 55 (95 %CI 41-not reached) months in patients who did not. High corticosteroid peak dose was associated with worse PFS and OS (HR adj 1.14; 95 %CI 1.01-1.29; HR adj 1.29; 95 %CI 1.12-1.49 for 80vs40mg), while cumulative dose was not. Second-line immunosuppression was associated with worse PFS (HR adj 1.32; 95 %CI 1.02-1.72) and OS (HR adj 1.34; 95 %CI 0.99-1.82) compared with corticosteroids alone., Conclusions: High corticosteroid peak dose and second-line immunosuppressants to treat irAEs are both associated with impaired survival. While immunosuppression is indispensable for treatment of severe irAEs, clinicians should weigh possible detrimental effects on survival against potential disadvantages of undertreatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GAPH reports consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, Merck Sharp and Dome, Pfizer, Novartis, Sanofi, Pierre Fabre and has received research funding from Bristol-Myers Squibb and Seerave. All paid to institution. MJBA reports consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Novartis, Merck Sharp and Dome, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas and Bayer, and received research funding from Merck-Pfizer. All paid to institution. KC reports consultancy fees from Eli Lilly AbbVie and Pfizer. ATJM has received fees from AbbVie, Actelion, CSL Behring, Experf, Novartis, and Shire and declares speaking fees from AstraZeneca, Sanofi-Aventis and Bristol-Myers Squibb. CUB reports consulting/advisory relationships with AstraZeneca, Bristol-Myers Squibb, GenMab, GSK, Lilly, Merck Sharp and Dome, Novartis, Pfizer, Pierre Fabre, Roche and Third Rock Ventures, and received research funding from 4SC, Bristol-Myers Squibb, NanoString and Novartis. All paid to institution. His is co-founder of and owns shares in Immagene BV and Signature Oncology, and is inventor on several related patents (including submitted): WO 2021/177822 A1, N2027907 and P091040NL2. SA reports consulting/advisory relationships with Merck Sharp and Dome, Sanofi, Roche, Bristol-Myers Squibb, Pfizer, Ipsen and Galapagos. All paid to institution. DP reports consultancy/advisory relationships with Pierre Fabre and Novartis. Partly paid to intstitution. EK reports consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Pierre Fabre, Immunocore and Lilly, and received research grants not related to this paper from Bristol Myers Squibb, Delcath, Novartis and Pierre-Fabre. Not related to current work and paid to institute. ML reports consultancy/advisory relationships with Bristol-Myers Squibb and Janssen-Cilag B.V. All paid to institution. AMMvdV reports consultancy/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Sanofi, Pfizer, Novartis, Roche, Eisai, Merck, Pierre Fabre and Ipsen. All paid to institution. JBAGH reports consultancy/advisory relationships with Achillus Tx, AstraZenica, BioNTech, Bristol-Myers Squibb, CureVac, GlaxoSmithKline, Imcyse, Iovance Bio, Instil Bio, Ipsen, Merck, Merck Sharp and Dome, Molecular Partners, Neogene TX, Novartis, Pfizer, PokeAcell, Roche, Sanofi, Scenic, T-Knife and TRV, and received research funding from Amgen, Bristol-Myers Squibb, BioNTech, Merck Sharp and Dome, Novartis and Sastra Cell Therapy. All paid to institution. KPMS reports consulting/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Abbvie, Pierre Fabre, Novartis, Sairopa. She received honoraria from Novartis and Merck Sharp and Dome, and research funding from TigaTx, Bristol Myers Squibb, Philips and Genmab. All paid to institution. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: CB has received grants or contracts from Bristol Myers Squibb, Novartis, NanoString, and 4SC unrelated to this manuscript; consulting fees from or participation on an advisory board of Bristol Myers Squibb, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, Pierre Fabre, and Third Rock Ventures; is a co-founder of Immagene BV and Signature Oncology; and holds the following patents WO 2021/177822 A1, N2027907, P091040NL2 (from the Netherlands; on combination therapies comprising antibody molecules to PD-1, interleukin-2 gene signature, and a sensor for adrenocortical insufficiency). AH is on the advisory board of NFU-ZN quickscan. All other authors declare no competing interests.

Purpose: The introduction of immune checkpoint inhibitors and targeted therapies improved the overall survival of patients with advanced melanoma. It is not known how often these costly treatments with potential serious side effects are ineffectively applied in the last phase of life. This study aimed to investigate the start of a new systemic therapy within 45 and 90 days of death in Dutch patients with advanced melanoma., Methods: We selected patients who were diagnosed with unresectable IIIC or stage IV melanoma, registered in the Dutch Melanoma Treatment Registry, and died between 2013 and 2019. Primary outcome was the probability of starting a new systemic therapy 45 and 90 days before death. Secondary outcomes were type of systemic therapy started, grade 3/4 adverse events (AEs), and the total costs of systemic therapies., Results: Between 2013 and 2019, 3,797 patients with unresectable IIIC or stage IV melanoma were entered in the registry and died. The percentage of patients receiving a new systemic therapy within 45 and 90 days before death was significantly different between Dutch melanoma centers (varying from 6% to 23% and 20% to 46%, respectively). Thirteen percent of patients (n = 146) developed grade 3/4 AEs in the last period before death. The majority of patients with an AE required hospital admission (n = 102, 69.6%). Mean total costs of systemic therapy per cohort year of the patients who received a new systemic therapy within 90 days before death were 2.3%-2.8% of the total costs spent on melanoma therapies., Conclusion: The minority of Dutch patients with metastatic melanoma started a new systemic therapy in the last phase of life. However, the percentages varied between Dutch melanoma centers. Financial impact of these therapies in the last phase of life is relatively small., Competing Interests: Rawa K. IsmailEmployment: MSD John B. HaanenStock and Other Ownership Interests: Neogene TherapeuticsConsulting or Advisory Role: MSD Oncology (Inst), Pfizer (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Roche/Genentech (Inst), Ipsen (Inst), Achilles Therapeutics (Inst), Immunocore (Inst), Sanofi (Inst), Third Rock Ventures (Inst), Neogene Therapeutics, Molecular Partners (Inst), bioNTech (Inst), T-Knife (Inst), PokeAcell (Inst), Instil Bio (Inst), Iovance Biotherapeutics (Inst)Research Funding: MSD (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Neon Therapeutics (Inst), Amgen (Inst), BioNTech (Inst), Asher Biotherapeutics (Inst) Christian U. BlankStock and Other Ownership Interests: ImmageneConsulting or Advisory Role: Roche/Genentech (Inst), MSD Oncology (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), AstraZeneca (Inst), Lilly (Inst), Pierre Fabre (Inst), GenMab (Inst), Third Rock VenturesResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), NanoString Technologies (Inst), 4SC (Inst)Patents, Royalties, Other Intellectual Property: WO 2021/177822 A1Expert Testimony: FreshfieldsTravel, Accommodations, Expenses: Bristol Myers Squibb Maureen J.B. AartsResearch Funding: Pfizer (Inst) Jan Willem B. de GrootConsulting or Advisory Role: Bristol Myers Squibb, Pierre Fabre, Servier Geke A.P. HospersConsulting or Advisory Role: Roche (Inst), MSD (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Pierre Fabre (Inst), Sanofi (Inst)Research Funding: Bristol Myers Squibb (Inst), Seerave Foundation (Inst) Ellen KapiteijnConsulting or Advisory Role: Pierre Fabre (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Lilly (Inst), Ipsen (Inst), Delcath Systems (Inst)Research Funding: BMS (Inst), Pierre Fabre (Inst) Djura PiersmaConsulting or Advisory Role: Pierre Fabre (Inst), Novartis (Inst) Astrid A.M. van der VeldtConsulting or Advisory Role: Ipsen (Inst), Roche (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst), MSD Oncology (Inst), Sanofi (Inst), Pierre Fabre (Inst), Novartis (Inst), Eisai (Inst), Merck (Inst)Research Funding: Bayer (Inst)Travel, Accommodations, Expenses: Roche, MSD Oncology, Novartis, Bayer Karijn P.M. SuijkerbuijkConsulting or Advisory Role: Bristol Myers Squibb (Inst), Novartis (Inst), MSD (Inst), Pierre Fabre (Inst), AbbVie (Inst)Speakers' Bureau: Roche (Inst), Novartis (Inst)Research Funding: Bristol Myers Squibb Foundation (Inst), TigaTx (Inst), Philips Research (Inst) Alfonsus J.M. van den EertweghHonoraria: Bristol Myers SquibbConsulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, Pierre FabreResearch Funding: Roche, Sanofi, BMSNo other potential conflicts of interest were reported.

Background: Recent reports suggest the limited efficacy of immune checkpoints inhibitors in advanced acral melanoma (AM). This study aims to investigate the clinical outcomes of immune checkpoint inhibitors in patients with stage III and IV AM and compare them to cutaneous melanoma (CM)., Methods: We included patients with advanced AM and CM treated with first-line anti-programmed cell death (PD)-1 monotherapy or ipilimumab-nivolumab registered in the prospective nationwide Dutch Melanoma Treatment Registry. Objective response rates, progression-free survival (PFS) and overall survival (OS) were calculated. A Cox proportional hazard model was used to assess the prognostic factors with PFS and OS., Results: In total, 2058 patients (88 AM and 1970 CM) with advanced melanoma were included. First-line objective response rates were 34% for AM versus 54% for CM in the advanced anti-PD-1 cohort and 33% for AM versus 53% for CM in the advanced ipilimumab-nivolumab cohort. The Median PFS was significantly shorter for anti-PD-1 treated AM patients (3.1 months; 95%CI: 2.8-5.6) than patients with CM (10.1 months; 95%CI: 8.5-12.2) (P < 0.001). In patients with advanced melanoma, AM was significantly associated with a higher risk of progression (HRadj 1.63; 95%CI: 1.26-2.11; P < 0.001) and death (HRadj 1.54; 95%CI: 1.15-2.06; P = 0.004) than CM., Conclusions: This study shows lower effectiveness of anti-PD -1 monotherapy and ipilimumab-nivolumab in AM, with lower response rates, PFS and OS than CM. This group of patients should be prioritised in the development of alternative treatment strategies., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AvdE has advisory relationships with Amgen, Bristol Myers Squibb, Roche, Novartis, MSD, Pierre Fabre, Sanofi, Pfizer, Ipsen, Merck and has received research study grants not related to this paper from Sanofi, Roche, Bristol Myers Squibb, Idera and TEVA and has received travel expenses from MSD Oncology, Roche, Pfizer and Sanofi and has received speaker honoraria from BMS and Novartis. JH has advisory relationships with Achilles Therapeutics, AstraZeneca, Bristol Myers Squibb, BioNTech, Immunocore, Iovance Biotherapeutics, Ipsen, MSD, Merck Serono, Molecular Partners, Novartis, Neogene Therapeutics, Pfizer, PokeAcel, Roche/Genentech, Sanofi, Third Rock Ventures, T-Knife and has received research grants not related to this paper from Asher Bio, Amgen, Bristol Myers Squibb, MSD, BioNTech, Neogene Therapeutics and Novartis. All grants were paid to the institutions. CB has received commercial research grants from Novartis, BristolMyers Squibb, and NanoString; is a paid advisory board member for Bristol Myers Squibb, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, and Pierre Fabre; and holds ownership interest in Uniti Cars, Neon Therapeutics, and Forty Seven. MA has advisory board/consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas, Bayer. Research grants Merck-Pfizer. Not related to current work and paid to institute. JdG has consultancy/advisory relationships with Bristol Myers Squibb, Pierre Fabre, Servier, MSD, Novartis. GH consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Roche, MSD, Pfizer, Novartis, Pierre Fabre and has received research grants not related to this paper from Bristol Myers Squibb, Seerave and were paid to the institution. EK has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly and Bayer, and received research grants not related to this paper from Bristol Myers Squibb. RvR has advisory board/consultancy honoraria from Pfizer and an expert meeting fee from Roche. AvdV has consultancy relationships with Bristol Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Pfizer, Sanofi, Ipsen, Eisai, Merck. MBS has consultancy/advisory relationships with Pierre Fabre, MSD and Novartis. KS has advisory relationships with Bristol Myers Squibb, Novartis, MSD, Pierre Fabre, AbbVie and received honoraria from Novartis, MSD and Roche. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1 blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral blood. If the activation of circulating, tumor-reactive T cells would form an important mechanism of action of PD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 T cell responses toward 71 melanoma-associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the circulating melanoma-reactive CD8 T cell response was unaltered upon PD-1 blockade. In contrast, a broadening of the circulating melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. Based on these results, we conclude that PD-1 and CTLA-4 blockade have distinct mechanisms of action. In addition, the data provide an argument in favor of the hypothesis that anti-PD-1 therapy may primarily act at the tumor site., Competing Interests: The authors declare no competing interest.

Introduction: In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increasingly treated with local therapy. We evaluated the role of local therapy for solitary progression in melanoma., Patients and Methods: Patients with metastatic melanoma treated with ICI between 2010 and 2019 with solitary progression as first progressive event were included from 17 centres in 9 countries. Follow-up and survival are reported from ICI initiation., Results: We identified 294 patients with solitary progression after stable disease in 15%, partial response in 55% and complete response in 30%. The median follow-up was 43 months; the median time to solitary progression was 13 months, and the median time to subsequent progression after treatment of solitary progression (TTSP) was 33 months. The estimated 3-year overall survival (OS) was 79%; median OS was not reached. Treatment consisted of systemic therapy (18%), local therapy (36%), both combined (42%) or active surveillance (4%). In 44% of patients treated for solitary progression, no subsequent progression occurred. For solitary progression during ICI (n = 143), the median TTSP was 29 months. Both TTSP and OS were similar for local therapy, ICI continuation and both combined. For solitary progression post ICI (n = 151), the median TTSP was 35 months. TTSP was higher for ICI recommencement plus local therapy than local therapy or ICI recommencement alone (p = 0.006), without OS differences., Conclusion: Almost half of patients with melanoma treated for solitary progression after initial response to ICI had no subsequent progression. This study suggests that local therapy can benefit patients and is associated with favourable long-term outcomes., Competing Interests: Conflict of interest statement All authors declare no direct conflict with this work. For unrelated conflicts, K.P.M.S. has an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, AbbVie and Pierre Fabre and has received honoraria from Merck Sharp & Dohme, Novartis and Roche. L.Z. has an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Sun Pharma; has received research funding from Novartis; has received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre and Roche and has received travel support from Amgen, Bristol Myers Squibb, Novartis, Pierre Fabre, Sanofi and Sun Pharma. E.W.K. has an advisory role for Bristol Myers Squibb, Merck, Novartis and Pierre Fabre; has received research funding from Bristol Myers Squibb and has received travel support from Roche. C.A. has received travel support from Amgen, Bristol Myers Squibb and Roche. D.B.J. has an advisory role for Array BioPharma, Bristol Myers Squibb, Incyte, Merck and Novartis; has received research funding from Bristol Myers Squibb and Incyte and has received travel support from Genentech. Adriana H. is an employee of AstraZeneca with stock options in the company, has received honoraria from Novartis; has an advisory role for L.E.K. Consulting and has received travel support from Roche. J.M. has received honoraria from Amgen, Bristol Myers Squibb, Merck-Pfizer, MSD, Novartis and Pierre Fabre; has an advisory role for Amgen, Merck-Pfizer, Merck Sharp & Dohme, Novartis and Pierre Fabre and has received travel support from Bristol Myers Squibb, L'Oreal, MSD, Pierre Fabre and Ultrasun. P.B. has received travel support from MSD. Y.J.L.J. has received travel support from Bristol Myers Squibb, MSD and Pfizer. V.A. has received honoraria from Bristol Myers Squibb, Genentech, Merck Serono, Merck Sharp & Dohme, Novartis and Pierre Fabre; has an advisory role for Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre and Roche and has received travel support from Bristol Myers Squibb, Merck Sharp & Dohme, OncoSec and Pierre Fabre. P.A.A. has an advisory role for 4SC, Alkermes, Amgen, Array BioPharma, Bristol Myers Squibb, Genentech, Genmab, Idera, Immunoscore, Incyte, Italfarmaco, MedImmune, Merck Serono, Merck Sharp & Dohme, Nektar, NewLink Genetics, Novartis, Pierre Fabre, Sandoz, Sanofi, Sun Pharma, Syndax and Ultimovacs; has received research funding from Array BioPharma, Bristol Myers Squibb and Genentech; has received travel support from Merck Sharp & Dohme and is a stockowner of PrimeVax. Andrew H. has received honoraria from Merck and Novartis and has an advisory role for Novartis and Pierre Fabre. A.M.M. has an advisory role for Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre and Roche. G.V.L. is a consultant advisor for Aduro Biotech, Inc., Amgen Inc., Array BioPharma Inc., Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Highlight Therapeutics S.L., Merck Sharp & Dohme, Novartis Pharma AG, QBiotics Group Limited, Regeneron Pharmaceuticals, Inc. and SkylineDX B.V. C.L. had received honoraria from Amgen, Bristol Myers Squibb, Incyte, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre and Roche; has an advisory role for Amgen, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Roche and Sanofi; has received research funding from Bristol Myers Squibb and Roche and has received travel support from Bristol Myers Squibb and Merck Sharp & Dohme. A.A.M.v.d.V. has an advisory role for Bristol Myers Squibb, Eisai, Ipsen, MSD Oncology, Merck, Novartis, Pfizer, Pierre Fabre, Roche and Sanofi and has received research funding from Bayer and travel support from Bayer, MSD Oncology, Novartis and Roche. M.S.C. has an advisory role for Amgen, Bristol Myers Squibb, Eisai, IDEAYA Biosciences, Merck and Co, Merck Sharp & Dohme, Nektar, Novartis, Pierre Fabre, Roche, Sanofi and QBiotics and has received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme and Novartis. S.S. has received honoraria from AstraZeneca, Bristol Myers Squibb, Merck and Merck Serono; has an advisory role for Amgen, Bristol Myers Squibb, MSD, Novartis and Roche outside the submitted work and has received research funding from Amgen, AstraZeneca, Endocyte, Genentech and Merck Sharp & Dohme. E.G.E.d.V. has an advisory role for Daiichi Sankyo, NSABP and Sanofi; has received research funding from Amgen, AstraZeneca, Bayer, Chugai Pharma, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier and Synthon and is the chair of ESMO Cancer Medicines Working Group, chair of RECITS committee and member of the ESMO-MCBS working group. C.U.B. has received research funding from Bristol Myers Squibb, Novartis and NanoString; has an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, Genmab and Pierre Fabre and is a stockowner of Uniti Cars. M.J. has an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, AstraZeneca, Tesaro and Pierre Fabre., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Inhibitors of the PD-1-PD-L1 axis have been approved as therapy for many human cancers. In spite of the evidence for their widespread clinical activity, little is known about the immunological alterations that occur in human cancer tissue after PD-1 blockade. We developed and employed a patient-derived tumor fragment platform to dissect the early immunological response of human tumor tissue to ex vivo PD-1 blockade. We observed that the capacity of immune cells to be reactivated ex vivo was predictive of clinical response, and perturbation analyses identified tumor-resident T cells as a key component of this immunological response. In addition, through combined analysis of baseline properties and immune response capacity, we identified a new subgroup of infiltrated tumors that lacks the capacity to respond to PD-1 blockade. Finally, the baseline presence of tertiary lymphoid structures and their components correlated with the capacity of cancers to undergo intratumoral immune cell reactivation., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The Italian Network for Tumor Biotherapy (Network Italiano per la Bioterapia dei Tumori [NIBIT]) Foundation hosted its annual 2020 Think Tank meeting virtually, at which representatives from academic, clinical, industry, philanthropic, and regulatory organisations discussed the role of neoadjuvant immunotherapy for the treatment of cancer. Although the number of neoadjuvant immunotherapeutic trials is increasing across all malignancies, the Think Tank focused its discussion on the status of neoadjuvant trials in cutaneous melanoma (CM), muscle-invasive urothelial bladder cancer (MIBC), head and neck squamous cell carcinoma (HNSCC), and pancreatic adenocarcinoma (PDAC). Neoadjuvant developments in CM are nothing short of trailblazing. Pathologic Complete Response (pCR), pathologic near Complete Response, and partial Pathologic Responses reduce 90-100% of recurrences. This is in sharp contrast to targeted therapies in neoadjuvant CM trials, where only a pCR seems to reduce recurrence. The pCR rate after neoadjuvant immunotherapy varies among the different malignancies of CM, MIBC, HNSCC, and PDAC and may be associated with different reductions of recurrence rates. In CM, emerging evidence suggests that neoadjuvant immunotherapy with anti-CTLA-4 plus anti-PD1 is a game changer in patients with palpable nodal Stage III or resectable Stage IV disease by curing more patients, reducing recurrences and the need for surgical interventions, such as lymph node dissections and metastasectomies. The Think Tank panel discussed future approaches on how to optimise results across different tumour types. Future approaches should include reducing monocyte-mediated (tumour-associated macrophages) and fibroblast-mediated (cancer-associated fibroblasts) barriers in the tumour microenvironment to facilitate the recruitment of immune cells to the tumour site, to reduce immune-suppressive mediators, and to increase antigen presentation at the site of the tumour., Competing Interests: Conflicts of interest statement M.M. was a consultant/advisory board member for Bristol Myers Squibb, Roche, Astra Zeneca, Merck Sharp Dohme, Philogen, Merck Serono, Glaxo Smith Kline, Sanofi, Pierre Fabre, Eli-Lilly, Amgen, Cosmos, Alfasigma, and owns shares of Epigen Therapeutics. C.B. received commercial research grants from Novartis, Bristol-Myers Squibb, and NanoString; is a paid advisory board member for Bristol-Myers Squibb, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, and Pierre Fabre; and holds ownership interest in Uniti Cars, Neon Therapeutics, and Forty Seven. A.N. received honoraria Roche, Merck, AstraZeneca, and Janssen Pharmaceuticals. A.M.D.G. was a consultant and/or advisor to Incyte, Pierre Fabre, Bristol Myers Squibb, Merck Sharp Dohme, and Sanofi and has received compensated educational activities from Bristol Myers Squibb, Merck Sharp Dohme, Pierre Fabre, and Sanofi. R.I. was a CMO at bitbio, BoD of bluebird and Surface oncology, and SAB member of Harpoon. M.L. was employed by iOnctura SA as Chief Medical Officer. B.F. received consulting fees from Turnstone Bio, PrimeVax, UltiVue, AstraZeneca, and Boehringer Ingelheim; conducted contracted research at Macrogenics, OncoSec, BMS, Akoya, NanoString, Incyte, Shimadzu, and Viralytics/Merck; was cofounder of and holds ownership interest in UbiVac. R.B.B. has received research funds from Bristol-Myers Squibb and is on the speakers bureau for Merck and Regeneron. He is an advisory board member for Macrogenics. G.T. was a consultant/advisory board member for Bristol Myers Squibb, Astra Zeneca, Merck Sharp Dohme, and Merck Serono. A.M.M.E. is/has been consultant/advisory board member for Biocad, BioInvent, BioNTech, BMS, CatalYm, Ellipses, GSK, ISA pharmaceuticals, Ellipses, GSK, IO Biotech, ISA pharmaceuticals, Merck&Co/MSD, Nektar, Novartis, Pfizer, Roche, Sellas, SkylineDx, RiverD, TigaTx, and TTxDiscovery., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1)., Methods: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1., Findings: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5-30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7-34·8]) than with ipilimumab monotherapy (8·8 months [6·1-11·3]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6-3·6]) than with ipilimumab (2·6 months [2·4-2·9]; HR 0·69, 95% CI 0·55-0·87; p=0·0019). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis., Interpretation: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma., Funding: None., Competing Interests: Declaration of interests IPdS reports personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, and Roche, outside the submitted work. ABW reports personal fees from Shanghai Jo'Ann Medical Technology, Nanobiotix, Novartis, LG Chem Life Sciences, and Iovance, outside the submitted work. CA reports personal fees from Roche, Amgen, and Bristol Myers Squibb, outside the submitted work. JM reports grants, personal fees, and travel grants from Bristol Myers Squibb and Merck Sharp & Dohme; personal fees from Merck Sharp & Dohme, Pfizer, Sanofi, Amgen, and Novartis; personal fees and travel grants from Pierre Fabre; and travel grants from Ultrasun and Loreal, outside the submitted work. LZ reports personal fees, advisory board participation, and travel grants from Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Roche, and Novartis; and advisory board participation and travel grants from Sanofi and Amgen, outside the submitted work. ML reports personal fees from Bristol Myers Squibb, Novartis, Roche, and Merck Sharp & Dohme, outside the submitted work. OK and AH report personal fees from Bristol Myers Squibb and Merck Sharp & Dohme, outside the submitted work. OM reports grants and personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Pierre-Fabre, and Amgen; personal fees from Roche, Novartis, and GlaxoSmithKline; and grants from Merck Sharp & Dohme, outside the submitted work. PAA reports grants and personal fees from Bristol Myers Squibb, Roche, Array BioPharma, and Sanofi; personal fees from Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, and Lunaphore; and uncompensated consultant service from Takis, outside the submitted work. MSC reports personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen, Sanofi, Merck Serono, Pierre Fabre, Roche, Ideaya, Regeneron, Nektar, Eisai, Qbiotics, and Oncosec, outside the submitted work. CL reports grants and personal fees from Bristol Myers Squibb and Roche; personal fees from Merck Sharp & Dohme, Novartis, Amgen, Avantis Medical Systems, Pierre Fabre, Pfizer, Incyte, Merck Serono, and Sanofi, outside the submitted work. PL reports personal fees and support for travel from Merck Sharp & Dohme and Novartis; personal fees from Amgen, Nektar, and Pierre Fabre; and grants, personal fees, and support for travel from Bristol Myers Squibb, outside the submitted work. DBJ reports being part of advisory boards and consulting for Array Biopharma, Catalyst, Iovance, Jansen, Merck Sharp & Dohme, Novartis, and Oncosec; grants and other research funding from Bristol Myers Squibb; and grants from Incyte, outside the submitted work. SS reports grants from Novartis, AstraZeneca, Merck Sharp & Dohme, and Genentech; and personal fees from AstraZeneca, Merck Sharp & Dohme, and Bristol Myers Squibb, outside the submitted work. CUB reports grants from an advisory role in Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, Pierre Fabre, and Third Rock Ventures; research funding from Bristol Myers Squibb, Novartis, and NanoString; stock ownership in Uniti cars; and is a cofounder of Immagene, outside the submitted work. AMM reports personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and QBiotics, outside the submitted work. GVL reports personal fees from Amgen, Array Biopharma, Boehringer Ingelheim, Bristol Myers Squibb, Hexal, Highlight Therapeutics, Merck Sharp & Dohme, Novartis, Pierre Fabre, QBiotics, Regeneron Pharmaceuticals, and Specialised Therapeutics Australia, outside the submitted work. TA, ILMR, AMW, JRP, PS-B, KN, CT, DS, CLG, and SNL declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Because immune checkpoint inhibition (ICI) can cause immune-related adverse events (irAEs) mimicking immunologic diseases, patients with preexisting autoimmune disease (AID) have been excluded from clinical trials., Objective: To evaluate the safety and efficacy of ICI in patients with advanced melanoma with and without AID., Design: Nationwide cohort study., Setting: The Netherlands., Patients: 4367 patients with advanced melanoma enrolled in the Dutch Melanoma Treatment Registry (DMTR) between July 2013 and July 2018 and followed through February 2019., Measurements: Patient, clinical, and treatment characteristics; irAEs of grade 3 or higher; treatment response; and survival., Results: A total of 415 patients (9.5%) had AID, categorized as rheumatologic AID ( n = 227), endocrine AID ( n = 143), inflammatory bowel disease (IBD) ( n = 55), or "other" ( n = 8). Of these, 228 patients (55%) were treated with ICI (vs. 2546 [58%] without AID); 87 were treated with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), 187 with anti-programmed cell death 1 (PD-1), and 34 with the combination. The incidences of irAEs of grade 3 or higher in patients with AID were 30% (95% CI, 21% to 41%) with anti-CTLA-4, 17% (CI, 12% to 23%) with anti-PD-1, and 44% (CI, 27% to 62%) with combination therapy; for patients without AID, the incidences were 30% (CI, 27% to 33%) ( n = 916), 13% (CI, 12% to 15%) ( n = 1540), and 48% (CI, 43% to 53%) ( n = 388), respectively. Patients with AID more often discontinued anti-PD-1 treatment because of toxicity than patients without AID (17% [CI, 12% to 23%] vs. 9% [CI, 8% to 11%]). Patients with IBD were more prone to anti-PD-1-induced colitis (6/31 = 19% [CI, 7% to 37%]) than patients with other AIDs (3% [CI, 0% to 6%]) and patients without AID (2% [CI, 2% to 3%]).The objective response rate was similar in patients with versus without AID who were treated with anti-CTLA-4 (10% [CI, 5% to 19%] vs. 16% [CI, 14% to 19%]), anti-PD-1 (40% [CI, 33% to 47%] vs. 44% [CI, 41% to 46%]), or the combination (39% [CI, 20% to 59%] vs. 43% [CI, 38% to 49%]). Survival did not differ between patients with and those without AID (median, 13 months [CI, 10 to 16 months] vs. 14 months [CI, 13 to 15 months])., Limitation: Information was limited on AID severity and immunosuppressive treatment., Conclusion: Response to ICI with anti-CTLA-4, anti-PD-1, or their combination for advanced melanoma and overall incidence of any irAEs of grade 3 or higher were similar in patients with and without preexisting AID. However, severe colitis and toxicity requiring early discontinuation of treatment occurred more frequently among patients with preexisting IBD, warranting close follow-up., Primary Funding Source: The Netherlands Organization for Health Research and Development.

Background: Adjuvant targeted therapy (TT) improves relapse free survival in patients with resected BRAF mutant stage III melanoma. The outcomes and optimal management of patients who relapse after adjuvant TT is unknown., Methods: Patients from twenty-one centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined., Results: Eighty-five patients developed recurrent melanoma; nineteen (22%) during adjuvant TT. Median time to first recurrence was 18 months and median follow-up from first recurrence was 31 months. Fifty-eight (68%) patients received immunotherapy (IT) or TT as 1st line systemic therapy at either first or subsequent recurrence and had disease that was assessable for response. Response to anti-PD-1 (±trial agent), combination ipilimumab-nivolumab, TT rechallenge and ipilimumab monotherapy was 63%, 62% 25% and 10% respectively. Twenty-eight (33%) patients had died at census, all from melanoma. Two-year OS was 84% for anti-PD-1 therapy (±trial agent), 92% for combination ipilimumab and nivolumab, 49% for TT and 45% for ipilimumab monotherapy (p = 0.028)., Conclusions: Patients who relapse after adjuvant TT respond well to subsequent anti-PD-1 based therapy and have outcomes similar to those seen when first line anti-PD-1 therapy is used in stage IV melanoma.

Background: Patients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer., Methods: We analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality., Findings: Thirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off., Interpretation: COVID-19-related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19., Competing Interests: Competing interests: MiM: consultant/advisor for Bristol Myers Squibb, MSD, Novartis, Roche, Pierre Fabre. AANR: fellowship funding from Alamos Gold Inc. JMG: project focused consultant/advisor for Merck/Pfizer, MSD, Amgen, Novartis, Bristol Myers Squibb and Pierre Fabre; travel support from Ultrasun, L’Oreal, MSD, Bristol Myers Squibb and Pierre Fabre outside of the submitted work. TPM: fellowship funding from Alamos Gold Inc. SDS: consultant/advisor for Janssens, Novartis and Sanofi. AMM: consultant/advisor to Bristol Myers Squibb, MSD, Novartis, Roche, Pierre Fabre and QBiotics. MSC: consultant/advisor for Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, Sanofi, Merck, Ideaya, Regeneron, Nektar, Eisai; honoraria from Bristol Myers Squibb, MSD, Novartis. CB: consultant/advisor for Amgen, Bristol Myers Squibb, MSD, Novartis Pharma AG, Regeneron Pharmaceuticals Inc, Roche Pharma, Sanofi Aventis. LiZ: consultant/advisor for Bristol Myers Squibb, Novartis, Pierre Fabre, Sunpharma, Sanofi, MSD; research funding from Novartis; travel support from Bristol Myers Squibb, Pierre Fabre, Sanofi, Amgen, Novartis, Sunpharma. DS: consultant/advisor for Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Merck Serono, Amgen, Immunocore, Incyte, 4SC, Pierre Fabre, Mologen and Sanofi/Regeneron; honoraria from Roche/Genentech, Novartis, MSD, Bristol Myers Squibb, Merck Serono, Amgen, Immunocore, Incyte, 4SC, Pierre Fabre, Sysmex, Grünenthal Group, Agenus, Array BioPharma, AstraZeneca, LEO Pharma, Pfizer, Philogen, Regeneron and Mologen; travel/accommodation expenses from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Serono, Amgen and Merck; speakers bureau for Novartis, Bristol Myers Squibb, MSD, Amgen, Incyte, Pierre Fabre and Roche; research funding from Novartis and Bristol Myers Squibb; steering committee membership for Novartis, MSD and Bristol Myers Squibb. AH: consultant/advisor for Amgen, Bristol Myers Squibb, MSD/Merck, Pfizer, NeraCare, Novartis, Philogen, Pierre Fabre, Roche and Regeneron/Sanofi-Genzyme. RD: intermittent, project focused consulting and/or advisory relationships with Novartis, MSD, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, MaxiVAX SA and touchIME outside the submitted work. JH: consultant/advisor for AIMM, AchillesTx, Bristol Myers Squibb, BioNTech, GSK, Immunocore, Merck Serono, MSD, Neogene Tx, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures, Vaximm; research grants from Amgen, Bristol Myers Squibb, MSD, BioNTech, Novartis. CUB: consultant/advisor for Bristol Myers Squibb, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures; research funding from Bristol Myers Squibb, Novartis, NanoString; stock ownership: Uniti Cars; co-founder: Immagene BV. CR: consultant/advisor for Bristol Myers Squibb, MSD, Roche, Novartis, CureVac, Sanofi, Pierre Fabre. RJS: consultant/advisor for Asana Biosciences, Astrazeneca, Bristol Myers Squibb, Eisai, Iovnace, Pfizer, Merck, Novartis, Replimune; research funding: Amgen, Merck. PAA: consultant/advisory for Bristol Myers Squibb, Roche/Genentech, MSD, Novartis, Array, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron; research funding from Bristol Myers Squibb, Roche/Genentech, Array and travel support from MSD. FSH: consultancy/advisory for Bristol Myers Squibb, Merck, EMD Serono, Novartis, Surface, Compass Therapeutics, Apricity, Aduro, Sanofi, Pionyr, 7 Hills Pharma, Torque, Rheos, Kairos, Bicara, Psioxus Therapeutics, Pieris Pharmaceutical, Zumutor, Corner Therapeutics, Idera, Takeda, Genentech/Roche, Bioentre, Gossamer. KPMS: consulting/advisory for Bristol Myers Squibb, MSD, Abbvie, Pierre Fabre, Novartis; honoraria received from Novartis, Roche, MSD (all paid to institution). KLR: consultant/advisor for Teladoc. OER: consultant/advisor for Merck, Celgene, Five Prime, GSK, Bayer, Roche/Genentech, Puretech, Imvax, Sobi; research support from Merck; speaker for activities supported by educational grants from Bristol Myers Squibb and Merck; patent “Methods of using pembrolizumab and trebananib” pending. PCL: consultant/advisor for Bristol Myers Squibb, MSD, Pierre Fabre, Novartis, Amgen and Roche; travel support from Bristol Myers Squibb and MSD; research support from Bristol Myers Squibb. MaM: consultant advisor for Bristol Myers Squibb, MSD, Novartis, Roche, PierreFabre. GVL: consultant/advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Highlight Therapeutics SL, MSD, Novartis Pharma AG, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX BV, all declarations of interest are outside of the submitted work. AR, IPS, CT, CAT, JMG, MHT, SN, LZ, PB, AE, NP, MGV, JB, SR, TC, JL, AV, MOB, ME, LP, PQ, CP, WHM, RDC and SL have no conflict of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The T-cell response is regulated by the balance between costimulatory and coinhibitory signals. Immune checkpoints are essential for efficient T-cell activation, but also for maintaining self-tolerance and protecting tissues from damage caused by the immune system, and for providing protective immunity. Modulating immune checkpoints can serve diametric goals, such that blocking a coinhibitory molecule can unleash anti-cancer immunity whereas stimulating the same molecule can reduce an over-reaction in autoimmune disease. The purpose of this review is to examine the regulation of T-cell costimulation and coinhibition, which is central to the processes underpinning autoimmunity, transplant rejection and immune evasion in cancer. We will focus on the immunomodulation agents that regulate these unwanted over- and under-reactions. The use of such agents has led to control of symptoms and slowing of progression in patients with rheumatoid arthritis, reduced rejection rates in transplant patients, and prolonged survival in patients with cancer. The management of immune checkpoint inhibitor treatment in certain challenging patient populations, including patients with pre-existing autoimmune conditions or transplant patients who develop cancer, as well as the management of immune-related adverse events in patients receiving antitumor therapy, is examined. Finally, the future of immune checkpoint inhibitors, including examples of emerging targets that are currently in development, as well as recent insights gained using new molecular techniques, is discussed. T-cell costimulation and coinhibition play vital roles in these diverse therapeutic areas. Targeting immune checkpoints continues to be a powerful avenue for the development of agents suitable for treating autoimmune diseases and cancers and for improving transplant outcomes. Enhanced collaboration between therapy area specialists to share learnings across disciplines will improve our understanding of the opposing effects of treatments for autoimmune disease/transplant rejection versus cancer on immune checkpoints, which has the potential to lead to improved patient outcomes., (Copyright © 2020. Published by Elsevier Ltd.)

BRAF + MEK inhibition is preferentially applied as first-line therapy in BRAF V600-mutated melanoma patients with unfavourable prognostic features, due to the ability of targeted therapy (TT) to induce rapid symptom control, decrease tumour burden and normalize lactate dehydrogenase (LDH) levels. In addition, short-term TT transiently increases tumour antigen presentation and tumour influx of T cells. Therefore, it might be favourable to switch TT to checkpoint inhibition (CPI) before progression (PD). We retrospectively analysed melanoma patients treated first line with TT (TT1) and who subsequently switched to CPI during response to TT (sDR group) or at progression upon TT (sPD group). We identified 74 patients (n = 37 sDR group and n = 37 sPD group). ORR to CPI was 27.0% in the sDR group versus 24.3% in the sPD group (p = .790). Median was PFS 2.5 months versus 1.2 months (p = .145), and median OS was 30.6 versus 14.1 months (p = .007). After adjusting for baseline differences and known prognostic factors, hazard ratios (HRs) favouring sDR were 0.89 for PFS upon CPI (p = .956) and 0.48 for OS (p = .055). Thus, patients switching to CPI during ongoing clinical benefit from TT do not have an inferior outcome. Due to baseline imbalances and small patient population, a favourable trend for the sDR group can be hypothesized only., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Predicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to ICI, using routinely available clinical data including primary melanoma characteristics. We used a population‐based cohort of 3525 patients with advanced cutaneous melanoma treated with anti‐PD‐1‐based therapy. Our prediction model for predicting response within 6 months after ICI initiation was internally validated with bootstrap resampling. Performance evaluation included calibration, discrimination and internal–external cross‐validation. Included patients received anti‐PD‐1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. The model included serum lactate dehydrogenase, World Health Organization performance score, type and line of ICI, disease stage and time to first distant recurrence—all at start of ICI—, and location and type of primary melanoma, the presence of satellites and/or in‐transit metastases at primary diagnosis and sex. The over‐optimism adjusted area under the receiver operating characteristic was 0.66 (95% CI: 0.64–0.66). The range of predicted response probabilities was 7%–81%. Based on these probabilities, patients were categorized into quartiles. Compared to the lowest response quartile, patients in the highest quartile had a significantly longer median progression‐free survival (20.0 vs 2.8 months; P <.001) and median overall survival (62.0 vs 8.0 months; P <.001). Our prediction model, based on routinely available clinical variables and primary melanoma characteristics, predicts response to ICI in patients with advanced melanoma and discriminates well between treated patients with a very good and very poor prognosis. [ABSTRACT FROM AUTHOR]

Since the introduction of BRAF(/MEK) inhibition and immune checkpoint inhibition (ICI), the prognosis of advanced melanoma has greatly improved. Melanoma is known for its remarkably long time to first distant recurrence (TFDR), which can be decades in some patients and is partly attributed to immune‐surveillance. We investigated the relationship between TFDR and patient outcomes after systemic treatment for advanced melanoma. We selected patients undergoing first‐line systemic therapy for advanced melanoma from the nationwide Dutch Melanoma Treatment Registry. The association between TFDR and progression‐free survival (PFS) and overall survival (OS) was assessed by Cox proportional hazard regression models. The TFDR was modeled categorically, linearly, and flexibly using restricted cubic splines. Patients received anti‐PD‐1‐based treatment (n = 1844) or BRAF(/MEK) inhibition (n = 1618). For ICI‐treated patients with a TFDR <2 years, median OS was 25.0 months, compared to 37.3 months for a TFDR >5 years (P =.014). Patients treated with BRAF(/MEK) inhibition with a longer TFDR also had a significantly longer median OS (8.6 months for TFDR <2 years compared to 11.1 months for >5 years, P =.004). The hazard of dying rapidly decreased with increasing TFDR until approximately 5 years (HR 0.87), after which the hazard of dying further decreased with increasing TFDR, but less strongly (HR 0.82 for a TFDR of 10 years and HR 0.79 for a TFDR of 15 years). Results were similar when stratifying for type of treatment. Advanced melanoma patients with longer TFDR have a prolonged PFS and OS, irrespective of being treated with first‐line ICI or targeted therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Up to 50% of patients diagnosed with advanced melanoma develop brain metastases during the course of their disease. The prognosis of melanoma patients is heavily affected by the presence of brain metastases. Unfortunately, there is a lack of data on prognostic factors for these patients. Many of these patients are treated with immune checkpoint inhibitors. Therefore, the aim of our study was to identify prognostic factors in melanoma patients with brain metastases treated with immune checkpoint inhibitors. In a population of 1278 advanced melanoma patients, we found that serum lactate dehydrogenase levels were the strongest clinical parameter associated with survival. This information is useful for both doctors and patients to provide more insight into patients' prognoses. The efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma that develop brain metastases (BM) remains unpredictable. In this study, we aimed to identify prognostic factors in patients with melanoma BM who are treated with ICIs. Data from advanced melanoma patients with BM treated with ICIs in any line between 2013 and 2020 were obtained from the Dutch Melanoma Treatment Registry. Patients were included from the time of the treatment of BM with ICIs. Survival tree analysis was performed with clinicopathological parameters as potential classifiers and overall survival (OS) as the response variable. In total, 1278 patients were included. Most patients were treated with ipilimumab–nivolumab combination therapy (45%). The survival tree analysis resulted in 31 subgroups. The median OS ranged from 2.7 months to 35.7 months. The strongest clinical parameter associated with survival in advanced melanoma patients with BM was the serum lactate dehydrogenase (LDH) level. Patients with elevated LDH levels and symptomatic BM had the worst prognosis. The clinicopathological classifiers identified in this study can contribute to optimizing clinical studies and can aid doctors in giving an indication of the patients' survival based on their baseline and disease characteristics. [ABSTRACT FROM AUTHOR]

Simple Summary: BRAF/MEK therapy and anti-PD-1 therapy have shown better recurrence-free survival of stage III melanoma in patients with BRAF V600 mutations in clinical trials. However, little is known about how these therapies compare to each other in everyday practice. The aim of our study was to describe the toxicity and survival of patients treated with BRAF/MEK therapy and anti-PD-1 therapy in daily practice. We demonstrated that grade ≥ 3 toxicity occurred in 11.5% of patients and was the most common cause of early treatment discontinuation (71.1%). We also show that at 12 months, patients treated with BRAF/MEK therapy have less progression than those treated with anti-PD-1 therapy. However, this is no longer the case at 18 months. Adjuvant BRAF/MEK- and anti-PD-1 inhibition have significantly improved recurrence-free survival (RFS) compared to placebo in resected stage III BRAF-mutant melanoma. However, data beyond the clinical trial setting are limited. This study describes the toxicity and survival of patients treated with adjuvant BRAF/MEK inhibitors and compares outcomes to adjuvant anti-PD-1. For this study, stage III BRAF V600 mutant cutaneous melanoma patients treated with adjuvant BRAF/MEK-inhibition or anti-PD-1 were identified from the Dutch Melanoma Treatment Registry. BRAF/MEK- and anti-PD-1-treated patients were matched based on propensity scores, and RFS at 12 and 18 months were estimated. Between 1 July 2018 and 31 December 2021, 717 patients were identified. Of these, 114 patients with complete records were treated with BRAF/MEK therapy and 532 with anti-PD-1. Comorbidities (p = 0.04) and geographical region (p < 0.01) were associated with treatment choice. In 45.6% of BRAF/MEK-treated patients, treatment was prematurely discontinued. Grade ≥ 3 toxicity occurred in 11.5% of patients and was the most common cause of early discontinuation (71.1%). At 12 and 18 months, RFS in BRAF/MEK-treated patients was 85% and 70%, compared to 68% and 68% in matched anti-PD-1-treated patients (p = 0.03). In conclusion, comorbidities and geographical region determine the choice of adjuvant treatment in patients with resected stage III BRAF-mutant melanoma. With the currently limited follow-up, BRAF/MEK-treated patients have better RFS at 12 months than matched anti-PD-1-treated patients, but this difference is no longer observed at 18 months. Therefore, longer follow-up data are necessary to estimate long-term effectiveness. [ABSTRACT FROM AUTHOR]

Simple Summary: Nodular melanoma is associated with a higher locoregional recurrence rate and worse overall survival outcomes. Whether this histologic subtype affects the efficacy of immunotherapy or targeted therapy is unclear. The aim of our multi-center nationwide study is to identify the efficacy of immunotherapy and BRAF/MEKi therapy in metastatic nodular melanoma compared with the efficacy in metastatic superficial spreading melanoma. Our study results demonstrate no difference between the effectiveness of immunotherapy and BRAF/MEKi in metastatic nodular versus superficial melanoma patients. A shorter distant metastasis-free survival and reduced overall survival (measured as the time between primary melanoma up to death or last follow-up) was observed in the nodular melanoma patient group, suggesting worse overal survival of nodular melanoma is mainly driven by propensity of metastatic outgrowth of nodular melanoma after primary diagnosis. Nodular melanoma (NM) is associated with a higher locoregional and distant recurrence rate compared with superficial spreading melanoma (SSM); it is unknown whether the efficacy of systemic therapy is limited. Here, we compare the efficacy of immunotherapy and BRAF/MEK inhibitors (BRAF/MEKi) in advanced NM to SSM. Patients with advanced stage IIIc and stage IV NM and SSM treated with anti-CTLA-4 and/or anti-PD-1, or BRAF/MEKi in the first line, were included from the prospective Dutch Melanoma Treatment Registry. The primary objectives were distant metastasis-free survival (DMFS) and overall survival (OS). In total, 1086 NM and 2246 SSM patients were included. DMFS was significantly shorter for advanced NM patients at 1.9 years (CI 95% 0.7–4.2) compared with SSM patients at 3.1 years (CI 95% 1.3–6.2) (p < 0.01). Multivariate survival analysis for immunotherapy and BRAF/MEKi demonstrated a hazard ratio for immunotherapy of 1.0 (CI 95% 0.85–1.17) and BRAF/MEKi of 0.95 (CI 95% 0.81–1.11). A shorter DMFS for NM patients developing advanced disease compared with SSM patients was observed, while no difference was observed in the efficacy of systemic immunotherapy or BRAF/MEKi between NM and SSM patients. Our results suggests that the worse overall survival of NM is mainly driven by propensity of metastatic outgrowth of NM after primary diagnosis. [ABSTRACT FROM AUTHOR]

Background: In the previously reported primary analyses of this phase 3 trial, 12 months of adjuvant pembrolizumab resulted in significantly longer recurrence- and distant metastasis-free survival than placebo in patients with resected high-risk stage III melanoma. To confirm the stability of these benefits, longer-term data were needed. Methods: We randomly assigned 1019 patients to receive 200 mg of pembrolizumab or placebo intravenously every 3 weeks for a total of 18 doses (approximately 1 year) and had previously reported data with a 15-, 36-, and 42-month median follow-up. We now report data at a median follow-up of 4.9 years. We report a number of outcomes, including recurrence-free survival in the overall population and in the subgroup of patients with cancer who were positive for the programmed death-ligand 1 (PD-L1). Distant metastasis-free survival was a secondary end point. Results: In the overall intention-to-treat population, pembrolizumab was still associated with longer recurrence-free survival than placebo (5-year rate of recurrence-free survival, 55.4% [95% confidence interval (CI), 50.8 to 59.8] vs. 38.3% [95% CI, 33.9 to 42.7]; hazard ratio for recurrence or death, 0.61 [95% CI, 0.51 to 0.72]) and a longer distant metastasis-free survival (5-year rate of distant metastasis-free survival, 60.6% [95% CI, 56.0 to 64.9] vs. 44.5% [95% CI, 39.9 to 48.9]; hazard ratio for distant metastasis or death, 0.62 [95% CI, 0.52 to 0.75]). Similar findings were obtained in the subgroup of 853 patients with PD-L1-positive tumors. Conclusions: The 5-year analysis of adjuvant therapy with pembrolizumab resulted in a sustained improvement in the long-term recurrence- and distant metastasis-free survival compared with placebo in patients with resected stage III melanoma. (Funded by Merck & Co., Inc.; ClinicalTrials.gov number, NCT02362594, and EudraCT number, 2014-004944-37.) [ABSTRACT FROM AUTHOR]

PURPOSE: Little is known about the effect of specific gene mutations on efficacy of immune checkpoint inhibitors in patients with advanced melanoma. MATERIALS AND METHODS: All patients with advanced melanoma treated with first-line anti–PD-1 or ipilimumab-nivolumab between 2012 and 2021 in the nationwide Dutch Melanoma Treatment Registry were included in this cohort study. Objective response rate, progression-free survival (PFS), and overall survival (OS) were analyzed according to BRAF and NRAS status. A multivariable Cox model was used to analyze prognostic factors associated with PFS and OS. RESULTS: In total, 1764 patients received anti–PD-1 and 759 received ipilimumab-nivolumab. No significant differences in PFS were found in the anti–PD-1 cohort. In the ipilimumab-nivolumab cohort, median PFS was significantly higher for BRAF -mutant melanoma (9.9 months; 95% CI, 6.8 to 17.2) compared with NRAS -mutant (4.8 months; 95% CI, 3.0 to 7.5) and double wild-type (5.3 months; 95% CI, 3.6 to 7.1). In multivariable analysis, BRAF -mutant melanoma was significantly associated with a lower risk of progression or death in the ipilimumab-nivolumab cohort. Median OS was significantly higher for BRAF -mutant melanoma compared with NRAS -mutant and double wild-type melanoma for both immune checkpoint inhibitor regimens. CONCLUSION: Ipilimumab-nivolumab–treated patients with BRAF -mutant melanoma display improved PFS and OS compared with patients with NRAS -mutant and double wild-type melanoma. BRAF mutation status is a factor to consider while choosing between mono and dual checkpoint inhibition in advanced melanoma. Ipilimumab-nivolumab–treated patients with BRAF-mutant melanoma have improved PFS and OS compared with BRAF WT patients [ABSTRACT FROM AUTHOR]

Advances in immune checkpoint and combination therapy have led to improvement in overall survival for patients with advanced melanoma. Improved understanding of the tumor, tumor microenvironment and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. Combination modalities with other immunotherapy agents, chemotherapy, radiotherapy, electrochemotherapy are also being explored to overcome resistance and to potentiate the immune response. In addition, novel approaches such as adoptive cell therapy, oncogenic viruses, vaccines and different strategies of drug administration including sequential, or combination treatment are being tested. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic theràapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers, but they have yet to be fully characterized and implemented clinically. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. Overall, the future research efforts in melanoma therapeutics and translational research should focus on several aspects including: (a) developing robust biomarkers to predict efficacy of therapeutic modalities to guide clinical decision-making and optimize treatment regimens, (b) identifying mechanisms of therapeutic resistance to immune checkpoint inhibitors that are potentially actionable, (c) identifying biomarkers to predict therapy-induced adverse events, and (d) studying mechanism of actions of therapeutic agents and developing algorithms to optimize combination treatments. During the Melanoma Bridge meeting (December 2nd-4th, 2021, Naples, Italy) discussions focused on the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine as well as the impact of COVID-19 pandemic on management of melanoma patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included in these trials. The aim of this study was to describe the treatment patterns and outcomes of "real-world" older patients with metastatic melanoma. We included 2216 patients aged ≥65 years from the Dutch Melanoma Treatment Registry and described outcomes of immunotherapy. The study showed that responses and severe side effects did not differ from previously reported younger populations and randomized trials, even in the oldest patients and in patients with other diseases. However, patients aged ≥75 discontinued treatment due to toxicity more often, resulting in fewer treatment cycles. We therefore conclude that immunotherapy seems to have similar effects in older patients compared to younger patients, but the impact of less severe toxicity on quality of life should be further studied as older patients are more likely to discontinue treatment. Background: Previous trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included. The aim of this study was to describe the treatment patterns and outcomes of "real-world" older patients with metastatic melanoma and to identify predictors of outcome. Methods: We included patients aged ≥65 years with metastatic melanoma from the Dutch Melanoma Treatment Registry. We described the reasons for hospital admissions and treatment discontinuation. Additionally, we assessed predictors of toxicity and response using logistic regression models and survival using Cox regression models. Results: We included 2216 patients. Grade ≥3 toxicity was not associated with age, comorbidities or WHO status. Patients aged ≥75 discontinued treatment due to toxicity more often, resulting in fewer treatment cycles. Response rates were similar to previous trials (40.3% and 43.6% in patients aged 65–75 and ≥75, respectively, for anti-PD1 treatment) and did not decrease with age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity. Conclusion: Response rates and toxicity outcomes of checkpoint inhibitors did not change with increasing age or comorbidity. However, the impact of grade I-II toxicity on quality of life deserves further study as older patients discontinue treatment more frequently. [ABSTRACT FROM AUTHOR]

In the previously reported primary analyses of this phase 3 trial, 12 months of adjuvant pembrolizumab resulted in significantly longer recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) than placebo in patients with resected high risk stage III melanoma. Stability of these benefits when the median follow-up was 3.5 and 5 years was published. Here we report results with a longer follow-up. We randomized 1019 patients to receive pembrolizumab 200 mg or placebo, intravenously every 3 weeks for a total of 18 doses. RFS in the overall population and in the subgroup of patients with melanoma positive for the PD-1 ligand (PD-L1) were co-primary endpoints. DMFS in these two populations was a secondary and progression/recurrence-free survival 2 (PRFS2) an exploratory endpoint. The median follow-up was 6.9 years. In the overall intention-to-treat population, RFS was longer in the pembrolizumab group than in the placebo group (HR 0.63, 95 % CI 0.53 to 0.74). RFS at 7 years was 50 % (95 % CI 46 % to 55 %) in the pembrolizumab and 36 % (95 % CI 32 % to 41 %) in the placebo group. Positive effects were present both for loco-regional recurrences and distant metastases, and across substages IIIA-IIIB-IIIC, and PD-L1 positive and PD-L1 negative as well as for BRAF mutant and BRAF wild type populations. DMFS was longer in the pembrolizumab group than in the placebo group (HR 0.64, 95 % CI 0.54 to 0.76). DMFS at 7 years was 54 % (95 % CI 50 % to 59 %) in the pembrolizumab and 42 % (95 % CI 37 % to 46 %) in the placebo group. PRFS2 was longer in the pembrolizumab group than in the placebo group (HR 0.69, 95 % CI 0.57 to 0.84). PRFS2 at 7 years was 61 % (95 % CI 57 % to 66 %) in the pembrolizumab and 53 % (95 % CI 49 % to 57 %) in the placebo group. The 7-year analysis of adjuvant therapy with pembrolizumab demonstrated a sustained improvement in the long-term RFS, DMFS and PRFS2 compared with placebo in patients with resected stage III melanoma. • One year of adjuvant pembrolizumab results in sustained prolongation of RFS at 7 years. • One year of adjuvant pembrolizumab results in sustained prolongation of DMFS at 7 years. • Similar benefits are observed across all subgroups of stage III melanoma patients. • Benefits are also maintained for adjuvant pembrolizumab for the PRFS2 endpoint. [ABSTRACT FROM AUTHOR]

Abstract Context The abysmal outlook of urothelial cancer (UC) has changed with the introduction of immunotherapy. Still, many patients do not respond and distinctive biomarkers are currently lacking. The rise of this novel armamentarium of immunotherapy treatments, in combination with the complex biology of an immunological tumor response, warrants the development of a comprehensive framework that can provide an overview of important immunological processes at play in individual patients. Objective To develop a comprehensive framework based on tumor- and host-specific parameters to understand immunotherapy response in UC. This framework can inform rational, biology-driven clinical trials and ultimately guide us toward individualized patient treatment. Evidence acquisition A literature review was conducted on UC immunotherapy, clinical trial data, and biomarkers of response to checkpoint inhibition. Evidence synthesis Here, we propose a UC immunogram, based on currently available clinical and translational data. The UC immunogram describes several tumor- and host-specific parameters that are required for successful immunotherapy treatment. These seven parameters are tumor foreignness, immune cell infiltration, absence of inhibitory checkpoints, general performance and immune status, absence of soluble inhibitors, absence of inhibitory tumor metabolism, and tumor sensitivity to immune effectors. Conclusions Longitudinal integration of individual patient parameters may ultimately lead to personalized and dynamic immunotherapy, to adjust to the Darwinian forces that drive tumor evolution. Incorporating multiparameter biomarkers into quantitative predictive models will be a key challenge to integrate the immunogram into daily clinical practice. Patient summary Here, we propose the urothelial cancer immunogram, a novel way of describing important immunological characteristics of urothelial cancer patients and their tumors. Seven characteristics determine the chance of having an immunological tumor response. Using this immunogram, we aim to better understand why some patients respond to immunotherapy and some do not, to ultimately improve anticancer therapy. Take Home Message Checkpoint inhibitors induce durable responses in a subset of urothelial cancer (UC) patients. A theoretical framework to understand immunotherapy response is warranted. Longitudinal integration of multiple parameters into the UC immunogram may ultimately lead to individualized immunotherapy to combat therapy resistance. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis. In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre. Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p =.007), confusion (83% vs. 43%; p =.02), disorientation (83% vs. 29%; p =.007) and aphasia (43% vs. 0%; p =.007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43). ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death. • Presentation of ICI-iE is variable and resembles that of HSV-1 encephalitis. • Abnormal MRI and antineuronal antibodies are less common than previously reported. • Analysis of cerebrospinal fluid has the highest diagnostic value in ICI-iE. • ICI-iE has a mortality of 10% and long-term sequelae occur in 47% of patients. • Early immunosuppressive treatment of ICI-iE is associated with full recovery. [ABSTRACT FROM AUTHOR]

Pain is common in patients with cancer. The World Health Organisation recommends paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for mild pain and combined with other agents for moderate/severe pain. This study estimated associations of NSAIDs with recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and the incidence of immune-related adverse events (irAEs) in high-risk patients with resected melanoma in the EORTC 1325/KEYNOTE-054 phase III clinical trial. Patients with AJCC7 stage IIIA, IIIB or IIIC resected melanoma were randomized to receive 200 mg of adjuvant pembrolizumab (N = 514) or placebo (N = 505) 3-weekly for one year or until recurrence. As previously reported, pembrolizumab prolonged RFS and DMFS. NSAID use was defined as administration between 7 days pre-randomization and starting treatment. Multivariable Cox and Fine and Gray models were used to estimate hazard ratios (HRs) for associations of NSAIDs with RFS, DMFS and irAEs. Of 1019 patients randomized, 59 and 44 patients in the pembrolizumab and placebo arms, respectively, used NSAIDs. NSAIDs were not associated with RFS (HR 0.91, 95% CI 0.58–1.43) or DMFS in the pembrolizumab (HR 1.03, 95% CI 0.65–1.66) or placebo arms (for RFS, HR 0.76, 95% CI 0.48–1.20; for DMFS, HR 0.80, 95% CI 0.49–1.31). NSAIDs were associated with the incidence of irAEs in the placebo arm (HR 3.06, 95% CI 1.45–6.45) but not in the pembrolizumab arm (HR 0.94, 95% CI 0.58–1.53). NSAIDs were not associated with efficacy outcomes nor the risk of irAEs in patients with resected high-risk stage III melanoma receiving adjuvant pembrolizumab. • NSAIDs were not associated with recurrence-free survival. • NSAIDs were not associated with distant metastasis-free survival. • NSAIDs were not associated with the incidence of immune-related adverse events. [ABSTRACT FROM AUTHOR]

Metformin is a commonly prescribed and well-tolerated medication. In laboratory studies, metformin suppresses BRAF wild-type melanoma cells but accelerates the growth of BRAF-mutated cells. This study investigated the prognostic and predictive value of metformin, including with respect to BRAF mutation status, in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 randomised controlled trial. Patients with resected high-risk stage IIIA, IIIB, or IIIC melanoma received 200 mg of pembrolizumab (n = 514) or placebo (n = 505) every 3 weeks for twelve months. Pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) at approximately 42 months median follow-up (Eggermont et al., TLO, 2021). Multivariable Cox regression was used to estimate associations of metformin with RFS and DMFS. Interaction terms were used to model effect modification by treatment and BRAF mutation. Fifty-four patients (0.5%) used metformin at baseline. Metformin was not significantly associated with RFS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.52–1.45) and DMFS (HR 0.82, 95% CI 0.47–1.44). The interaction between metformin and the treatment arm was not significant for either RFS (p = 0.92) or DMFS (p = 0.93). Among patients with mutated BRAF, the association of metformin with RFS (HR 0.70, 95% CI 0.37–1.33) was greater in magnitude though not significantly different to those without mutated BRAF (HR 0.98, 95% CI 0.56–1.69). There was no significant impact of metformin use on pembrolizumab efficacy in resected high-risk stage III melanoma. However, larger studies or pooled analyses are needed, particularly to explore a possible effect of metformin in BRAF-mutated melanoma. • In the EORTC 1325/KEYNOTE-054 phase III trial, concomitant use of Metformin. • Was not significantly associated with recurrence-free survival (RFS). • Did not alter the treatment difference regarding RFS. • Did not shorten RFS in BRAF-mutated melanoma, as suggested by preclinical data. [ABSTRACT FROM AUTHOR]